Deferoxamine (deferrioxamine or desferrioxamine) and its pharmaceutically-acceptable salts are chelating agents which exhibit high binding affinities for metal ions such as aluminum and ferric ions. Deferoxamine mesylate is commercially available and has been used to treat severe iron intoxication, iron storage disease or iron overload resulting from hemolysis due to drugs, thalassemia, sickle-cell anemia, frequent blood transfusions and the like. McLachian (U.S. Pat. No. 4,419,365) discloses the treatment of Alzheimer's disease by the administration of deferoxamine salts to increase aluminum excretion. Aluminum dialysis encephalopathy can also be reversed by treatment with deferoxamine, R. S. Arze et al., Lancet ii, 1116 (1981).
There are a number of problems with the clinical use of deferoxamine mesylate. Since the drug is not appreciably absorbed when orally administered, it generally must be given parenterally. Once administered, the drug is very rapidly excreted. For example, in humans the drug exhibits a half-life of only about 5-10 min. Chelation therapy with the drug, as a result, involves continuous infusion or frequent intramuscular injections, which may cause pain and/or induration at the injection site. Further, the acute and chronic toxicity of deferoxamine is relatively high, making the substance less versatile for therapeutic uses.
A need exists for an agent, useful in iron chelation therapy, that is resistant to in vitro or in vivo degradation and/or excretion. A further need exists for a method to prolong the effective lifetime of deferoxamine following in vivo administration. Also, a preferred deferoxamine agent having reduced toxicity is needed.
The substance deferoxamine is often abbreviated DFO or DES (not to be confused with diethylstilbesterol). For consistancy, only the abbreviation DFO will be used herein Terms such as "Dextran-DFO" mean an adduct of the polymer (dextran) with DFO. Such an adduct may include more than one DFO moiety per unit substrate.